In the past, several indole derivatives being substituted at the nitrogen atom with a carboxylic acid radical have been found to possess .[.analgetic.]. .Iadd.analgesic .Iaddend.and antiinflammatory properties. Recently it was suggested in German OLS No. 2811031 that also indoles having a phenylsubstituent at the nitrogen atom might have the desired .[.analgetic.]. .Iadd.analgesic .Iaddend.or antiinflammatory effects, but no data were given for the .[.1-phenyl-5-chloro-3-methylpiperanzineindole .Iadd.1-phenyl-5-chloro-3-(4-methyl-1-piperazinyl)-1-phenylindole or 1-phenyl-5-chloro-3-cyclohexyl-piperazineimdole actually disclosed in the specification. We have prepared the first-mentioned of these compound Lu23-015) and found that it was without interesting effects .Iadd.as compared to the closest related compound of the invention, i.e., 5-chloro-1-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)indole (Lu 23-011), .Iaddend.in the pharmacological testing carried out in our laboratories.
In European Patent application No. 80401005.6 some derivatives of tetrahydro-pyridinyl-indoles having at the 1-position either hydrogen or alkyl (1-3 C-atoms), were described as being neuroleptics. The pharmacological data given in the specification, however, indicate only weak to moderate neuroleptic activity.
We have prepared one of these compounds, .[.5-chloro-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyrid-4-yl)indol.]. .Iadd.5-chloro-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyrid-4-yl)indole .Iaddend.(Lu 23-143) and found that it was almost active compared with the compounds of Formula I.
It has now surprisingly been found that the novel indole derivatives of Formula I are potent dopaminergic antagonists in pharmacological tests.[., both in vivo and.]. in vitro.[.,.]. .Iadd.and many of them also in vivo, .Iaddend.as compared with well-known neuroleptics commonly used in the treatment of psychoses; and especially very long-lasting effects -- up to several days -- were observed with many of the compounds of Formula I. Additionally, most of the .[.the.]. indoles of Formula I are strong 5-HT antogonists both .[.periferically.]. .Iadd.peripherally .Iaddend.and centrally, which is considered to be important for the treatment of psychic disorders or cardiovascular diseases.
The terms lower alkyl, lower alkoxy, lower alkylthio and lower alkysulfonyl designate such groups having from one to four carbon atoms inclusive. Exemplary of such groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec.butyl, methoxy, ethoxy, propoxy, butoxy, methylthio, ethylthio, propylthio, methylsulfonyl, ethylsulfonyl, or the like.
The term lower alkenyl designates alkenyl groups having from two to four carbon atoms, for example ethenyl, 1-propenyl, 2-butenyl, or the like.
This invention also includes pharmaceutically acceptable salts of the compounds of Formula I formed with non-toxic acids. Such salts are easily prepared by methods known to the art.
The base is reacted with either the calculated amount of organic or inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is well-known to the art.
The compounds of Formula I as well as the pharmaceutically acceptable acid addition salts thereof may be administered both orally and parenterally, for example in the form of tablets, capsules, powders, syrups or solutions for injection.
Of the indoles of Formula I, those wherein R.sup.1 is chlorine, fluorine, trifluoromethyl, methyl, nitro or amino in the 5-position, R is phenyl substituted with fluroine in the 4'-or the 2'-position, R.sup.2 is methyl, hydroxyethyl or 3-hydroxypropyl, and A is as defined above, have shown especially favourable effects in the pharmacological testing, and also have few undesired side effects.
The invention moreover relates to a method for the preparation of the novel indoles of Formula I, which comprises
(a) reacting an indole derivative of the following formula: ##STR3## wherein R.sup.1 and R are as defined above, with a 4-piperidone of the formula: ##STR4## wherein R.sup.2 is as defined above, or
(b) reducing a compound of the following formula: ##STR5## wherein R.sup.1, R and R.sup.2 are as defined above, or
(c) reacting a compound of the following formula: ##STR6## wherein R.sup.1, R.sup.2 and A are defined above, with a compound of formula:
wherein R is as defined above and "hal" is halogen, in the presence of a metal catalyst, or
(d) reacting a compound of the following formula: ##STR7## wherein R.sup.1, R and A are as defined above, with a lower alkyl halide or an epoxide of formula ##STR8## wherein .[.R.]. .Iadd.R' .Iaddend.is hydrogen, methyl or ethyl, or
(e) reducing a compound of the following formula: ##STR9## wherein R.sup.1, R and A are as defined above and R.sup.4 is hydrogen, lower alkyl (1-3 C-atoms) or lower alkoxy (1-3 C-atoms), or
(f) heating a compound of the following formula: ##STR10## wherein R.sup.1 and R .Iadd.are .Iaddend.as defined above, with a piperazine of formula: ##STR11## wherein R.sup.2 is as defined above, or
(g) reducing a compound of the following formula: ##STR12## wherein R.sup.1, R and R.sup.2 are as defined above, with a suitable reducing agent, whereupon the indole of Formula I is isolated in the form of the free base or a pharmaceutically acceptable acid addition salt thereof, and if the group R.sup.2 contains one or two hydroxyl groups, if desired, acylating such a hydroxy group with a reactive derivative of an aliphatic carboxylic acid having from two to twenty-four carbon atoms, and isolating the ester formed as the free base or a pharmaceutically acceptable acid addition salt thereof.
In method (a) the reaction is performed under strong acidic conditions by heating. Trifluoroacetic acid or HCl in ethanol are preferred as acid catalysts. The starting compounds of Formula II are conveniently prepared according to procedures described in the literature, e.g. by reduction of R substituted isatins or oxindoles by a method described by H. Sirowej et al, in Synthesis 1972, 84, according to the following reaction scheme: ##STR13## Isatins and oxindoles are prepared by a .[.Fiedel-Craft.]. .Iadd.Friedel-Craft .Iaddend.ring closure under standard conditions from N-oxalylchloro-or N-(2-chloroacetyl) diphenylamines respectively. The compounds of Formula II may alternatively be prepared by arylation of N-unsubstituted indoles according to the method described by M.A. Khan and E.K. Rocha, Chem.Pharm.Bull. 25 (11), 3110-3114 (1977).
An alternative way of obtaining the intermediates of Formula II is that from an indoxyl-2-carboxylic ester as outlined below: ##STR14## in method (b) the reduction is preferably carried out at low hydrogen pressures (3 ato.) in the presence of platinum or palladium on carbon black.
In method (c) the arylation is preferably carried out at about 160.degree.-210.degree. C. in aprotic polar solvents as e.g. N-methyl-2-pyrrolidone or hexamethylphosphoric triamide with K.sub.2 CO.sub.3 as base and copper as a catalyst. In method (e) the reduction is preferably carried out with LiAlH.sub.4 in THF or diethylether or with diborane in THF.
Method (f) is a two step procedure in which compound VII first is decarboxyalkylated in the presence of an inorganic salt as e.g. LiCl or MgCl.sub.2 in a polar solvent as e.g. diglyme, hexamethylphosphoric triameide or N-methyl-2-pyrrolidone at elevated temperatures (120.degree.-150.degree. C.). Finally, the appropriate piperazine is added and the temperature raised to about 200.degree. C. and kept there until the corresponding indoxyle has disappeared according to TLC analysis. The compounds of Formula VII are conveniently prepared according to the procedures reported by P. C. Unangst and M. E. Carethers, J.Heterocyclic Chem. 21, 709 (1984).
In method (g) diborane in THF is conveniently used as a reducing agent. The compounds of Formula VIII are prepared from the corresponding R-substituted isatins according to the following reaction scheme: ##STR15## The methods of the invention shall be illustrated in the following by some examples, which may not be construed as limiting: